Freeze-drying, also known as lyophilization, is a process for drying high-quality products such as, for example, pharmaceuticals, biological materials such as proteins, enzymes, microorganisms, and in general any thermo- and/or hydrolysis-sensitive materials. Freeze-drying provides for the drying of the target product via sublimation of ice crystals into water vapor, i.e., via the direct transition of at least a portion of the water content of the product from the solid phase into the gas phase.
Freeze-drying processes in the pharmaceutical area can be employed, for example, for the drying of drugs, drug formulations, Active Pharmaceutical Ingredients (“APIs”), hormones, peptide-based hormones, carbohydrates, monoclonal antibodies, blood plasma products or derivatives thereof, immunological compositions including vaccines, therapeutics, other injectables and in general substances which otherwise would not be stable over a desired time span. In order that a product may be stored and shipped, the water (or other solvent) has to be removed prior to sealing the product in vials or containers for preservation of sterility and/or containment. In the case of pharmaceutical and biological products, the lyophilized product can be re-constituted later by dissolving the product in a suitable reconstituting medium (e.g., a pharmaceutical grade diluents) prior to, e.g., injection.
A freeze-dryer is generally understood as a process device which may, for example, be employed in a process line for the production of freeze-dried particles with sizes, for example, ranging from micrometers (μm) to millimeters (mm). Freeze-drying may be performed under arbitrary pressure conditions, e.g., atmospheric pressure conditions, but may also be efficiently performed (in terms of, for example, drying time scales) under vacuum conditions, i.e., defined low-pressure conditions, with which the skilled person is familiar.
Particles can be dried after filling into vials or containers. Generally, however, greater drying efficiency is achieved when particles are dried as bulkware, i.e., before any filling step. One approach for a bulkware freeze-dryer comprises employing a rotary drum for receiving the particles and keeping them under rotation during at least part of the freeze-drying process. The rotating drum mixes the bulk product which increases the effective surface area available for heat and mass transfer as compared to a drying the particles after they have been filled into vials or containers or as bulkware in stationary trays. Generally, bulk drum-based drying may efficiently lead to homogeneous drying conditions for the entire batch.
WO 2009/109 550 A1 describes a process for stabilizing a vaccine composition containing an adjuvant. The process comprises prilling and freezing of a formulation, and subsequent bulk freeze-drying and dry filling of the product into final recipients. The freeze-dryer may comprise pre-cooled trays which collect the frozen particles, and which are then loaded on pre-cooled shelves of the freeze-dryer. Once the freeze-dryer is cooled, a vacuum is pulled in the freeze-drying chamber to initiate sublimation of water from the pellets. Vacuum rotary drum drying is proposed as an alternative to tray-based freeze-drying.
Vapor sublimation can further be promoted by various measures intended to establish or maintain optimal process conditions such those concerning process pressure, temperature, humidity, etc., in the process volume. Optimum process temperature can be reached by cooling the process volume to about −40° C. to −60° C., for example. However, ongoing sublimation in the process volume tends to decrease the temperature further, which leads to a decrease in drying efficiency. Therefore the temperature has to be maintained within an optimum range during freeze-drying and a corresponding heating mechanism is required.
DE 196 54 134 C2 describes a device for freeze-drying products in a rotatable drum. The drum is filled with the bulk product. During freeze-drying, a vacuum is established inside the drum slowly rotating drum. The vapor released by sublimation from the product is drawn off the drum. The drum is heatable, specifically, the inner wall of the drum can be heated by a heating means provided outside the drum in an annular space between the drum and a chamber housing the drum. Cooling is achieved by inserting a cryogenic medium into the annular space.
Generally, drum wall mediated heat transfer has several disadvantages. For example, there is a tendency for particles to adhere (stick) to the inner surface of the drum, e.g., due to the high frozen water content at least at the beginning of the drying process and/or because of electrostatic interactions of particles with each other and/or with drum. Particles that stick to the drum wall take on the temperature of the inner wall. As a result, the maximum temperature of the heated wall is limited to a value where the product quality is not negatively affected, e.g., due to partial or total melting of the particles stuck thereto. Therefore, the stickiness or tackiness of the product has to be taken into account when designing a process line. This generally limits the proposition of heat transfer via the inner wall surface of a rotary drum and consequently lengthens the freeze-drying process since it is difficult to maintain the optimum drying temperature in the absence of other heating mechanisms.
Attempts have been to avoid the above-mentioned sticky particle effect. Designs have been proposed that seek to provide a heating source inside a rotating drum device. In one such design, U.S. Pat. No. 2,388,917 A or DE 20 2005 021 235 U1, an infrared (IR) radiation emitter is arranged inside the drum volume usually surrounded or at least partially covered by a protective shield means or the like. However, such a heating source can negatively affect product quality. For example, particles may fall off the rotating drum wall traverse the drum volume and by chance contact the operating heat emitter, despite various attempts to provide protective emitter shielding. Additionally, or alternatively, sublimation vapor drawn off the drum can carry particles through the process volume within the drum. A number of these particles once in flight can similarly come near enough to or actually contact the operating heat emitter. This can lead to a fraction of the product being partially or totally melted. As a further consequence, melted particles can stick to each other (agglomerate). As a still further consequence, melted particles can stick to the drum walls and/or emitter surface(s) etc. As a result, product quality can be negatively affected, and problems with operating the emitter can occur, and/or problems with subsequent cleaning and/or sterilization processes can occur. Furthermore, due to the different coefficients of thermal expansion inherent in the different construction materials typically used in the drums and emitter devices gaps can develop between components. This is particularly an issue when typical infrared emitters are used under vacuum process conditions inside the drum. Also, infrared heating sources are particularly difficult to clean or sterilize due to the mix of materials and the use of gaskets between components such as flanges and glass tubes.